Mitosis is the process of nuclear division in cukaryotic cells that produces two daughter cells from one parent cell. The daughter cells and the original parent cell have identical chromosomes and DNA. Cancer is a disease of mitosis. Cancer begins when a single cell is converted from a normal cell to a cancer cell. This is often due to a change in function of one of several genes that normally function to control cell growth. The cancer cells proliferate by repeated, uncontrolled mitosis, in contrast to normal cells which undergo only 20-50 generations of replication and then cease. A tumor is a mass of unhealthy cells that are dividing and growing in an uncontrolled way.
A microtubule is one of the hollow, tube-like filaments found in certain cell components such as the mitotic spindle. Each microtubule is composed of repeating subunits of the protein tubulin. Microtubules aggregate to form spindle fibers. During mitosis, cells use their spindle fibers to line up chromosomes, make copies of them, and divide into new cells with each daughter cell having a single set of chromosomes. Microtubules are the target of commonly used antimitotic or chemotherapeutic drugs, including taxoid drugs such as paclitaxel and docetaxel, vinca alkaloids such as vinblastine, vincristine, and vindesine, colchicine, colcemid, and nocadazol.
Paclitaxel is sold under the name TAXOL. It is a taxoid drug extracted from the bark of the Pacific yew tree that is used for the treatment of ovarian, breast, and Kaposi's sarcoma cancers. Paclitaxel works by blocking a cell's ability to break down the mitotic spindle during mitosis. Paclitaxel binds to the tubulin protein of microtubules, locking the microtubules in place and inhibiting their depolymerization (molecular disassembly). With the mitotic spindle still in place, a cell cannot divide into daughter cells. In contrast, drugs like the vinca alkaloids, colchicine, colcemid, and nocadazol block mitosis by keeping the mitotic spindle from being formed in the first place. These drugs bind to tubulin and inhibit polymerization, preventing cells from making the spindles they need to move chromosomes around as they divide.
Unfortunately, many human cancers are either completely resistant to chemotherapy or respond only transiently, after which they are no longer affected by commonly used antimitotic agents. This phenomenon is known as multidrug resistance (MDR) and is inherently expressed by some tumor types while others acquire MDR after exposure to chemotherapy. P-glycoprotein (PGP), also known as MDR1, is a 170 kD membrane-bound protein which has been implicated as a primary cause of MDR in tumors. PGP is a member of the ATP-binding cassette (ABC) transport protein superfamily. PGPs are efflux transporters found in the gut, gonads, kidneys, biliary system, brain, and other organs, which appear to have developed as a mechanism to protect the body from harmful substances. PGPs transport certain hydrophobic substances, including substances that are clinically therapeutic, into the gut, out of the brain, into urine, into bile, out of the gonads, and out of other organs. MRP1 is another ABC transport protein that is associated with MDR in tumors. MRP1 is a 190 kD integral membrane protein that serves a similar purpose as PGP.
Thus, there exists a need for a method of treatment that employs an antimitotic or antitumor agent capable of inhibiting mitosis in a wide variety of cells, including cells that are subject to MDR, particularly PGP- or MRP1-mediated MDR. There also exists a need for a method of treatment that employs an antimitotic or antitumor agent capable of restoring the sensitivity of a tumor to antimitotic agents following the onset of MDR.